The development of highly active anti-retroviral therapy with protease inhibitors (PIs) has been associated with metabolic abnormalities including disturbances in glucose metabolism, dyslipidemia, and fat distribution/lipodystrophy. However their cause is debated. Data show that not all of the metabolic effects of PIs are direct toxic effects, as some are due to restoration to health, reconstitution of immune system or changes in fat distribution. A role for NRTI is emerging. To design future HIV drugs that have the least metabolic effects it is necessary to determine which metabolic effects of these drugs are direct toxic drug effects vs. secondary to changes in disease status. Given the difficulty in dissecting out the different contributors in HIV-positive patients, we have begun studies of the metabolic effects of ARV in HIV-negative controls. We have evidence that the metabolic effects are drug-specific and not class-specific with independent effects of PIs on glucose and lipid metabolism. Our preliminary data suggest that PIs affect several pathways in glucose metabolism including peripheral insulin resistance, insulin secretion and hepatic glucose production. These three lesions are key contributors to the development of type 2 diabetes. Therefore we propose to test the effects of PIs and NRTIs as follows: Specific Aim 1a: To determine which Pls inhibit insulin secretion in humans. Specific Aim 1b: To determine which PIs acutely block insulin mediated glucose disposal in humans. Specific Aim 1c: To determine which PIs increase hepatic glucose production and to determine the mechanisms by quantifying gluconeogenesis and glycogenolysis. Specific Aim 2a: To demonstrate that in subjects with elements of Metabolic Syndrome compared to thin healthy controls, PIs induce more diabetes and impaired glucose tolerance on oral glucose tolerance testing. Specific Aim 2b: To determine if the effects of PIs in Metabolic Syndrome are more severe at the level of resistance to insulin-mediated glucose disposal, insulin secretion and hepatic glucose production. Specific Aim 3a: To demonstrate that NRTI combinations, alone or with a PI, affect glucose metabolism in HIV negative subjects using the OGTT in acute or four-week studies. Specific Aim 3b: To determine the mechanisms by which NRTI adversely affect glucose metabolism, we will assess their effects on insulin mediated glucose disposal, insulin secretion and/or hepatic glucose production.